Regulation of protein synthesis in ventricular myocytes by vasopressin. The role of sarcoplasmic/endoplasmic reticulum Ca2+ stores.
Protein synthesis in H9c2 ventricular myocytes was subject to rapid inhibition by agents that release Ca2+ from the sarcoplasmic/endoplasmic reticulum, including thapsigargin, ionomycin, caffeine, and arginine vasopressin. Inhibitions were attributable to the suppression of translational initiation and were coupled to the mobilization of cell-associated Ca2+ and the phosphorylation of eIF2alpha. Ionomycin and thapsigargin produced relatively stringent degrees of Ca2+ mobilization that produced an endoplasmic reticulum (ER) stress response. Translational recovery was associated with the induction of ER chaperones and resistance to translational inhibition by Ca2+-mobilizing agents. Vasopressin at physiologic concentrations mobilized 60% of cell-associated Ca2+ and decreased protein synthesis by 50% within 20-30 min. The inhibition of protein synthesis was exerted through an interaction at the V1 vascular receptor, was imposed at physiologic extracellular Ca2+ concentrations, and became refractory to hormonal washout within 10 min of treatment. Inhibition was found to attenuate after 30 min, with full recovery occurring in 2 h. Translational recovery did not involve an ER stress response but rather was derived from the partial repletion of intracellular Ca2+ stores. Longer exposures to vasopressin were invariably accompanied by increased rates of protein synthesis. Translational inhibition by vasopressin, but not by Ca2+-mobilizing drugs, was both preventable and reversible by treatment with phorbol ester, which reduced the extent of Ca2+ mobilization occurring in response to the hormone. Larger and more prolonged translational inhibitions occurred after down-regulation of protein kinase C. This report provides the first compelling evidence that hormonally induced mobilization of sarcoplasmic/endoplasmic reticulum Ca2+ stores is regulatory upon mRNA translation.
Reilly
B A
BA
Department of Pharmacology, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854, USA.
Brostrom
M A
MA
Brostrom
C O
CO
D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism; D006352:Heart Ventricles / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D009124:Muscle Proteins / Q000096:biosynthesis*; D010766:Phosphorylation; D014176:Protein Biosynthesis / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D014667:Vasopressins / Q000494:pharmacology*
D015852:Eukaryotic Initiation Factor-2; D009124:Muscle Proteins; D014667:Vasopressins; D011493:Protein Kinase C; D002118:Calcium